The deposition of amyloid-beta (Ass) deposition is thought to begin many years prior to the onset of clinical Alzheimer's disease, but until recently it was not possible to track the longitudinal accumulation of Ass in vivo. Cross-sectional autopsy series and recent PET studies using 11CPittsburgh Compound B (PiB) suggest that a large fraction of cognitively normal older individuals harbor amyloid pathology. Our preliminary cross-sectional PiB imaging data in 100 cognitively normal (CN) older individuals have demonstrated significant variability in the level and anatomic distribution of amyloid deposition. It remains unknown whether there is a specific threshold of amyloid pathology in these CN that will predict 1) further amyloid accumulation, 2) the emergence of abnormalities on structural and functional imaging consistent with preclinical AD, and 3) subsequent cognitive decline. This project will acquire longitudinal PiB imaging, FDG-PET, resting fMRI, and detailed neuropsychological assessments in 80 CN subjects every 2 years to investigate the temporal course and anatomic pattern of amyloid accumulation (Aim 1). We will also utilize a recently developed, high-sensitivity PET camera to determine if there is a gradual accumulation of amyloid deposition that is not currently detectable with existing standard cameras (Aim 2). Finally, we will relate longitudinal amyloid accumulation to other indicators of prodromal AD, including regional FDG hypometabolism, functional MRI default network disruption, hippocampal atrophy, cortical thinning, and cognitive decline (Aim 3). This study will capitalize on an existing cohort of well-characterized clinically normal older subjects, a strong multi-disciplinary team of investigators, and state-of-the-art imaging methodology to probe the link between amyloid accumulation and the earliest brain changes associated with preclinical AD. PUBLIC HEALTH RELEVANCE: The symptoms of Alzheimer's disease, a major threat to public health, are preceded by a period of brain amyloid accumulation of at least 10 years duration. The overall aim of this grant proposal is to improve our ability during the presymptomatic period to detect amyloid, to trace its accumulation at low levels, and to assess its impact on the brain, so that treatments may begin at an earlier stage of disease when damage is more limited. To accomplish this, we propose to re-enroll a group of older adults who have already participated in our amyloid research, to now undergo a set of follow-up brain scans and cognitive tests every two years. We propose to measure the buildup of amyloid over time with PiB PET and assess the impact on brain structure with MRI and function with FDG PET. We will also test a powerful new, high-sensitivity PET scanner that we predict will improve our detection of amyloid and permit us to better study it's earliest consequences.